This application requests a Varian 4 Tesla MRI/MRS(I) system to continue our 15-yr focus on investigation of neurodegenerative diseases (ND). Goals, to: 1) determine the pathophysiology of various ND including cross sectional and longitudinal changes of anatomic (i.e. spatial) patterns of brain structure, perfusion, and metabolites; 2) develop improved diagnostic methods which can be applied to clinical practice; 3) develop methods for staging and monitoring disease progression which can be used in treatment trials; and 4) detect ND at an early, preclinical stage so that preventative treatment can be effectively initiated. This is a continuation of collaborative work between MR physicists, who develop new MRI/MRS(I) techniques, and clinical investigators. We believe that we have done more MRI/MRS(I) of ND than any other group in the world (> 2500 subjects/ 8 yrs). Our physicists have developed many new MRS(I) techniques (pulse sequences, RF pulses, coils, data processing); this emphasizes their ability to develop 4T techniques aimed at ND. Our clinical collaborators have funded projects on normal aging, Alzheimer's disease, frontotemporal dementia, vascular dementia, Lewy Body disease, epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, post traumatic stress disorder, schizophrenia, bipolar disorder, HN, alcoholism, and gulf war illness. Each project uses quantified MRI/MRS(I) data together with clinical/cognitive measures to test hypotheses statistically. Benefits of an increased field from 1.5-4T: Improved sensitivity for MRI in detecting anatomical change because of increased contrast as well as improved perfusion and diffusion MRI due to longer T1; Improved MRS(I) because of 3-fold increased S/N, allowing increased accuracy, smaller voxels, and increased spectral dispersion, facilitating measurement of glutamate (implicated in neurodegeneration), GABA, and other metabolites. ND has growing importance because of the aging population. Improved understanding of ND has led to development of new treatments and clinical trials. This project will focus advanced MRI/MRS(I) techniques at 4T on ND in order to increase knowledge concerning pathophysiology of ND, improve diagnosis and treatment monitoring, and finally to detect ND before debilitating symptoms develop, allowing preventative measures. These expected results emphasize the practical outcome and significance of this research.